DESCRIPTION (Verbatim from the application): This proposal will study mechanisms through which the intestinal microvasculature supports the absorptive and secretory functions of the bowel. During nutrient absorption, the intestinal villus and submucosal layer interstitium becomes hypertonic due to NaCl absorption. This laboratory has demonstrated sodium hyperosmolarity stimulates nitric oxide formation in vessel walls and crypt gland cells in the submucosa. The increased nitric oxide (NO) detected with microelectrodes contributes to the arteriolar vasodilation associated with intestinal absorption. How sodium hyperosmolarity stimulates the endothelial cells to increase their NO formation in unknown. However, the mechanism is linked to a specific attribute of sodium rather than hyperosmolarity per se. Hyperosmolarity due to a non-permeable, non-electrolyte molecule, such as mannitol, is a poor stimulus both for NO formation and arteriolar dilation compared to equivalent sodium chloride hyperosmolarity. We propose that sodium ions enter the endothelial and crypt gland cells through the Na+ - K+ - 2Cl- cotransport system used to maintain cell volume and the Na+ - H+ antiport. The excess intracellular sodium would compromise extrusion of calcium ions, gradually elevating the calcium concentration that leads to increased NO formation. Isolated intestinal arterioles will be used to document the increased calcium ion concentration in endothelial cells during NaCl hyperosmolarity. We propose that crypt glands require a large increase in blood flow and oxygen extraction to support the elevated metabolic rate associated with active transport of a hypertonic, sodium-rich solution to the bowel lumen during intestinal absorption. As NO is both a potent secretagogue and vasodilator, if crypt glands form NO in response to NaCl hyperosmolarity, the NO would stimulate secretion of the hypertonic interstitial fluid to the bowel lumen and dilate blood vessels to increase oxygen delivery needed for active transport of ions. As NaCl hyperosmolarity also stimulates arteriolar and venular endothelial cells to increase NO formation, sodium hyperosmolarity acting through increased NO formation could help coordinate the complex microvascular, absorptive and secretory functions of the bowel during nutrient absorption.